The current application represents a Phase I SBIR Grant application by Inotek Corporation, proposing to establish a proof-of-concept of the involvement of poly (ADP-ribose) polymerase (PARP) activation in the pathogenesis of diabetic erectile dysfunction. As preliminary data we present evidence in cultured cells, showing that PARP activation plays a key role in the development of oxidant-mediated diabetic cardiovascular complications. We also present preliminary data demonstrating that PARP deficient mice and animals treated with PARP inhibitors are resistant for the development of suppressed nerve conduction velocity in diabetes models. We now have synthesized a potent PARP inhibitor as a lead developmental candidate agent. As diabetic erectile dysfunction develops on the background of diabetic vasculopathy and neuropathy, and both of these processes are improved or reversed by PARP inhibition, now we hypothesize that PARP may also play a role in the pathogenesis of diabetic erectile dysfunction. The central aim of our Phase I component is to perform proof-of-concept in vivo studies in diabetic rodents, to test whether PARP inhibition prevents the development of diabetic erectile dysfunction. Acute and chronic studies will be conducted, and the therapeutic window will be established. The studies will be complemented with preliminary long-term safety evaluation of our development compound WW-46. If these studies confirm that Inotek's PARP inhibitor is effective in improving erectile function in diabetes, a Phase II component will be triggered, which will focus on formal preclinical safety testing. [unreadable] [unreadable]